The BDNF Val66Met polymorphism serves as a potential marker of body weight in patients with psychiatric disorders.

Brain-derived neurotrophic factor (BDNF) is a predominant neurotrophic factor in the brain, indispensable for neuronal growth, synaptic development, neuronal repair, and hippocampal neuroplasticity. Among its genetic variants, the BDNF Val66Met polymorphism is widespread in the population and has been associated with the onset and aggravation of diverse pathologies, including metabolic conditions like obesity and diabetes, cardiovascular ailments, cancer, and an array of psychiatric disorders. Psychiatric disorders constitute a broad category of mental health issues that influence mood, cognition, and behavior. Despite advances in research and treatment, challenges persist that hinder our understanding and effective intervention of these multifaceted conditions. Achieving and maintaining stable body weight is pivotal for overall health and well-being, and the relationship between psychiatric conditions and body weight is notably intricate and reciprocal. Both weight gain and loss have been linked to varying mental health challenges, making the disentanglement of this relationship critical for crafting holistic treatment strategies. The BDNF Val66Met polymorphism's connection to weight fluctuation in psychiatric patients has garnered attention. This review investigated the effects and underlying mechanisms by which the BDNF Val66Met polymorphism moderates body weight among individuals with psychiatric disorders. It posits the polymorphism as a potential biomarker, offering prospects for improved monitoring and therapeutic approaches for mental illnesses.

Association between reduced plasma BDNF concentration and MMSE scores in both chronic schizophrenia and mild cognitive impairment.

Reduced brain derived neurotrophic factor (BDNF) concentration is reported to be associated with a cognitive decline in schizophrenia, depending on the stage of the disease. Aim of the study was to examine the possible association between plasma BDNF and cognitive decline in chronic stable schizophrenia and mild cognitive impairment (MCI). The study included 123 inpatients of both sexes with schizophrenia, 123 patients with MCI and 208 healthy control subjects. Cognitive abilities were assessed using mini mental state examination (MMSE), Clock Drawing test (CDT) and cognitive subscale of the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF concentration was determined using ELISA. BDNF concentration was lower in patients with schizophrenia and MCI compared to age-matched healthy controls and was similar in carriers of different BDNF Val/66Met genotypes. The MMSE and CDT scores were lower in patients with schizophrenia compared to healthy controls and subjects with MCI. Reduced plasma BDNF was significantly associated with lower MMSE scores in all subjects. BDNF concentration in patients with schizophrenia was not affected by clinical and demographic factors. BDNF Val66Met polymorphism was not associated with the MMSE scores in all participants. Further studies should include longitudinal follow-up and other cognitive scales to confirm these results and offer cognition-improving strategies to prevent cognitive decline in chronic schizophrenia.

Serum brain-derived neurotrophic factor, Val66Met polymorphism and open-label SSRI treatment response in Major Depressive Disorder.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been implicated in the therapeutic action of antidepressants and possibly in the pathophysiology of Major Depressive Disorder (MDD). Clinical studies of peripheral blood levels of BDNF in MDD have provided conflicting results, and there are also conflicting reports regarding the predictive value of peripheral BDNF levels for antidepressant treatment response. The present study investigated the association between serum BDNF levels, the BDNF Val66Met polymorphism (rs6265), clinical characteristics and SSRI treatment response. METHODS: This open-label clinical trial included 99 physically healthy, unmedicated MDD participants and 70 healthy controls. Following a baseline assessment, 53 of the MDD participants completed an eight-week, open-label course of SSRI antidepressant treatment. Serum BDNF levels and Hamilton Rating Scale for Depression (HDRS) ratings were examined at baseline and after eight weeks of treatment. Antidepressant response was defined as a decrease in HDRS ratings of > 50% from baseline to the end-of-treatment. Finally, serum BDNF levels and SSRI treatment response were compared between MDD participants who were heterozygous or homozygous for the Met allele ("Met-carriers") and individuals homozygous for the Val allele. RESULTS: Serum BDNF levels at baseline were significantly higher in the unmedicated MDD participants compared to healthy controls (15.90 ng/ml vs 13.75 ng/ml, t (167) = -2.041, p = 0.043). In a post-hoc analysis, this difference was seen in the female but not male participants (16.85 ng/ml vs 14.06 ng/ml, t (91) = -2.067, p = 0.042; 14.86 ng/ml vs 13.31 ng/ml, t (74) = -0.923, p = 0.359). Baseline serum BDNF levels were not associated with treatment responder status or with absolute change in depression ratings over the course of 8-week SSRI treatment (p = 0.599). In both Responders and Non-responders, no significant changes in serum BDNF levels were found over the 8-week period of SSRI-treatment (16.32 ng/ml vs 16.23 ng/ml, t (18) = 0.060, p = 0.953; 16.04 ng/ml vs 15.61 ng/ml, t (29) = 0.438, p = 0.665, respectively). Further, no differences were found in serum BDNF levels prior to treatment between MDD Met-carriers and MDD Val/Val homozygotes (15.32 ng/ml vs 16.36 ng/ml, t (85) = 0.747, p = 0.457), and no differences were found in post-treatment serum BDNF (F1,42= 0.031, p = 0.862). However, MDD Val/Val homozygotes showed significantly greater antidepressant responses at week 8 than did MDD Met-carriers (F1,46 = 4.366, p = 0.043). CONCLUSION: Our results do not support sufficient reliability of using peripheral BDNF to characterize depression or to predict antidepressant response in clinical use. The role of sex in moderating BDNF differences in depression, and the role of BDNF gene polymorphisms in predicting antidepressant response, remain to be further investigated. We conclude that, while central nervous system BDNF is likely involved in antidepressant efficacy and in aspects of MDD pathophysiology, its reflection in serum BDNF levels is of limited diagnostic or prognostic utility.

Associations of brain-derived neurotrophic factor rs6265 polymorphism and cognitive function in breast cancer survivors from a cross-sectional study.

BACKGROUND: Breast cancer survivors (BCS) often complain of cancer-related cognitive impairment (CRCI) during and even months after completing primary cancer treatments, particularly chemotherapy. The etiology of CRCI is unknown, but associations of CRCI with germline genetic polymorphisms have been reported, including Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism. The current study investigated the associations of specific BDNF rs6265 with CRCI. METHODS: Cancer-related cognitive impairment was assessed using subjective reports of cognitive symptoms (the version 1.0, 8-item short-forms of the Patient-Reported Outcomes Measurement Information System®) and computerized objective cognitive function scores (CANTAB®). BDNF rs6265 genotypes were determined from buccal swabs. The associations of specific BDNF rs6265 with CRCI were examined by either one-way analysis of variance or the Kruskal-Wallis test followed by post hoc tests and rank-based regression analysis. RESULTS: We examined 356 female BCS. The mean (SD) age was 55.6 (9.8) years old, the median (IQR) years since cancer diagnosis were 4.0 (6.0), and 331 (92.7%) were self-described as White. BCS carrying the Met/Met genotype showed poorer results on 'visual episodic memory and new learning' and 'spatial working memory and executive function.' This relationship was observed regardless of prior chemotherapy. CONCLUSION: Our findings suggest that carrying the BDNF rs6265 Met/Met genotype increases the risk for CRCI in BCS. These results are foundational in nature and provide important information to identify mechanisms underpinning CRCI.

Potential role of APOE ɛ4 allele as a modifier for the association of BDNF Val66Met polymorphisms and cognitive impairment in community-dwelling older adults.

Objective: To determine whether the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with cognitive impairment (CI) in community-dwelling Chinese older adults, and to investigate whether this relationship is modified by the Apolipoprotein E (APOE) ɛ4 allele. Methods: The study is a secondary analysis of 703 participants aged ≥60 years randomly enrolled from the Beijing Longitudinal Study of Aging II prospective cohort. The education-adjusted Mini-Mental State Examination and the Clinical Dementia Rating Scale were used to measure the cognitive performance of the subjects. The main effects and interactions (additive and multiplicative) of the BDNF Met and the APOE ε4 alleles on CI were estimated by logistic regression models. Results: In total, 84 out of 703 older adults aged ≥60 years old had CI. No significant difference was observed in the risk of CI between participants with the BDNF Met allele and that of subjects without the BDNF Met allele (p = 0.213; p = 0.164). Individuals carrying both the BDNF Met and APOE ε4 alleles had an almost 1.5-fold increased odds of CI compared with carriers of the BDNF Met allele but without the APOE ε4 allele. The additive association indicated a positive interaction of both BDNF Met and APOE ε4 alleles with wide CIs (p = 0.021; p = 0.018). Conclusion: The results suggest that the APOE ε4 allele may be a potential modifier for the association of the BDNF Val66Met polymorphism with CI in community-dwelling older adults.

[The relationship between the rs6265 polymorphism of the BDNF gene and the level of serum neurotrophic factor in patients with Parkinson's disease]. / Svyaz' polimorfizma rs6265 gena BDNF s urovnem syvorotochnogo neirotroficheskogo faktora u patsientov s bolezn'yu Parkinsona.

OBJECTIVE: To evaluate the clinical features and the level of serum brain-derived neurotrophic factor (BDNF) in groups of patients with Parkinson's disease (PD) differentiated by the genotypes of BDNF polymorphism (rs6265). MATERIAL AND METHODS: The level of serum BDNF in the biomarkers' multiplex panel of neurodegenerative diseases (HNDG3MAG-36K) was assessed in 134 PD patients. Allele discrimination was carried out by real-time PCR using TaqMan probes for the analysis of BDNF rs6265 polymorphism in groups of patients and controls (n=192) matched for sex, age and ethnicity. RESULTS: Comparing the distribution of rs6265 genotypes and alleles between groups of patients and controls no significant differences were found (p>0.05). Serum BDNF levels varied significantly by genotype (rs6265) among PD patients. Minimum mean serum BDNF level (320.1±164.6 pg/ml) was noted for individuals with the AA genotype, which significantly differs from the corresponding indicator among individuals with GA (2944.2±1590.6 pg/ml; p=0.0001) and GG genotypes (2949.4±1620.6 pg/ml; p=3.9×10-5). The concentration of BDNF significantly differed between patients with different forms of PD (p=0.0007) and increased as the stage of the disease progressed according to Hoehn and Yahr staging scale (p=1.0×10-6). CONCLUSION: The BDNF rs6265 polymorphism was not associated with the development of PD in the studied population. The variability of the mean serum BDNF level was established depending on the genotype of the BDNF polymorphism in PD patients and a number of clinical features.

Interaction of Brain-derived Neurotrophic Factor, Exercise, and Fear Extinction: Implications for Post-traumatic Stress Disorder.

Brain-Derived Neurotrophic Factor (BDNF) plays an important role in brain development, neural plasticity, and learning and memory. The Val66Met single-nucleotide polymorphism is a common genetic variant that results in deficient activity-dependent release of BDNF. This polymorphism and its impact on fear conditioning and extinction, as well as on symptoms of post-traumatic stress disorder (PTSD), have been of increasing research interest over the last two decades. More recently, it has been demonstrated that regular physical activity may ameliorate impairments in fear extinction and alleviate symptoms in individuals with PTSD via an action on BDNF levels and that there are differential responses to exercise between the Val66Met genotypes. This narrative literature review first describes the theoretical underpinnings of the development and persistence of intrusive and hypervigilance symptoms commonly seen in PTSD and their treatment. It then discusses recent literature on the involvement of BDNF and the Val66Met polymorphism in fear conditioning and extinction and its involvement in PTSD diagnosis and severity. Finally, it investigates research on the impact of physical activity on BDNF secretion, the differences between the Val66Met genotypes, and the effect on fear extinction learning and memory and symptoms of PTSD.

Brain-Heart Axis: Brain-Derived Neurotrophic Factor and Cardiovascular Disease-A Review of Systematic Reviews.

BACKGROUND: The brain-heart axis is an intra- and bidirectional complex that links central nervous system dysfunction and cardiac dysfunction. In recent decades, brain-derived neurotrophic factor (BDNF) has emerged as a strategic molecule involved in both brain and cardiovascular disease (CVD). This systematic review of systematic reviews aimed to (1) identify and summarize the evidence for the BDNF genotype and BDNF concentration in CVD risk assessment, (2) evaluate the evidence for the use of BDNF as a biomarker of CVD recovery, and (3) evaluate rehabilitation approaches that can restore BDNF concentration. METHODS: A comprehensive search strategy was developed using PRISMA. The risk of bias was assessed via ROBIS. RESULTS: Seven studies were identified, most of which aimed to evaluate the role of BDNF in stroke patients. Only two systematic reviews examined the association of BDNF concentration and polymorphism in CVDs other than stroke. CONCLUSIONS: The overall evidence showed that BDNF plays a fundamental role in assessing the risk of CVD occurrence, because lower BDNF concentrations and rs6265 polymorphism are often associated with CVD. Nevertheless, much work remains to be carried out in current research to investigate how BDNF is modulated in different cardiovascular diseases and in different populations.

Enhanced methamphetamine sensitisation in a rat model of the brain-derived neurotrophic factor Val66Met variant: Sex differences and dopamine receptor gene expression.

Brain-derived neurotrophic factor (BDNF) and the Val66Met polymorphism may play a role in the development of psychosis and schizophrenia. The aim of this study was to investigate long-term effects of methamphetamine (Meth) on psychosis-like behaviour and dopamine receptor and dopamine transporter gene expression in a novel rat model of the BDNF Val66Met polymorphism. At the end of a 7-day subchronic Meth treatment, female rats with the Met/Met genotype selectively showed locomotor hyperactivity sensitisation to the acute effect of Meth. Male rats showed tolerance to Meth irrespective of Val66Met genotype. Two weeks later, female Met/Met rats showed increased locomotor activity following both saline treatment or a low dose of Meth, a hyperactivity which was not observed in other genotypes or in males. Baseline PPI did not differ between the groups but the disruption of PPI by acute treatment with apomorphine was absent in Meth-pretreated Met/Met rats. Female Met/Met rats selectively showed down-regulation of dopamine D2 receptor gene expression in striatum. Behavioural effects of MK-801 or its locomotor sensitisation by prior Meth pretreatment were not influenced by genotype. These data suggest a selective vulnerability of female Met/Met rats to short-term and long-term effects of Meth, which could model increased vulnerability to psychosis development associated with the BDNF Val66Met polymorphism.

Interaction of Val66Met BDNF and 5-HTTLPR polymorphisms with prevalence of post-earthquake 27-F PTSD in Chilean population.

Post-traumatic stress (PTSD) disorder is a mental health condition that can occur after experiencing or witnessing a traumatic event. The 27-F earthquake that struck Chile in 2010 was one such event that had a significant impact on the mental health of the population. A study was conducted to investigate the prevalence of PTSD and its associated factors among survivors of this earthquake. The study was a longitudinal design, involving a sample of 913 patients aged 18 to 75 years who attended 10 Primary Care Centers in Concepción, Chile. The Composite International Diagnostic Interview (CIDI) was used to assess both depressive episodes (DE) and PTSD before and after the earthquake. The study also involved genotyping studies using saliva samples from the participants, specifically focusing on the Val66Met and 5-HTTLPR polymorphisms. Statistical analysis was performed to examine the association between different variables and the presence of PTSD. These variables included demographic factors, family history of psychiatric disorders, DE, childhood maltreatment experiences, and critical traumatic events related to the earthquake. The results showed that the incidence of post-earthquake PTSD was 11.06%. No significant differences were found between the groups of participants who developed post-earthquake PTSD regarding the Val66Met or 5-HTTLPR polymorphisms. However, a significant association was found between the concomitant diagnosis of DE and the development of post-earthquake PTSD. The presence of DE doubled the risk of developing post-earthquake PTSD. The number of traumatic events experienced also had a statistically significant association with an increased risk of developing post-earthquake PTSD. The study's limitations include the potential interference of different DE subtypes, the complexity of quantifying the degree of earthquake exposure experienced by each individual, and events entailing social disruption, such as looting, that can profoundly influence distress. In conclusion, the study found that PTSD following the 27-F earthquake in Chile was associated with a concomitant diagnosis of DE and the number of traumatic events experienced. The study did not find a significant association between PTSD and the Val66Met or 5-HTTLPR polymorphisms. The researchers recommend that mental health professionals should prioritize the detection and treatment of concomitant depressive episodes and exposure to critical traumatic events in survivors of disasters. They also suggest that further research is needed to better understand the relationship between genetic factors and post-disaster PTSD.

Impact of transcranial direct current stimulation on white matter microstructure integrity in mild cognitive impairment patients according to effect modifiers as risk factors for Alzheimer's disease.

Background: Little research exists on how individual risk factors for Alzheimer's disease (AD) affect the intermediate phenotype after transcranial direct current stimulation (tDCS), despite the importance of precision medicine-based therapeutic approaches. Objective: To determine how an application of sequential tDCS (2 mA/day, left dorsolateral prefrontal cortex, 10 sessions) affects changes in white matter (WM) microstructure integrity in 63 mild cognitive impairment (MCI) patients with effect modifiers such as Aß deposition, APOE ε4 carrier status, BDNF Val66Met polymorphism status, and sex. Methods: We examined individual effect modifier-by-tDCS interactions and multiple effect modifiers-by-tDCS interactions for diffusion metrics. We also evaluated the association between baseline Aß deposition and changes in WM microstructure integrity following tDCS. Results: We found that APOE ε4 carrier status and sex had a significant interaction with tDCS, resulting in increased fractional anisotropy (FA) in the right uncinate fasciculus (UF) after stimulation. Additionally, we observed multiple effect modifiers-by-tDCS interactions on WM integrity of the right UF, leading to a more pronounced increase in FA values in APOE ε4 carriers and females with Val66 homozygotes. Finally, baseline Aß deposition was positively associated with a difference in FA of the left cingulum in the hippocampal area, which showed a positive association with the changes in the score for delayed memory. Conclusion: Our study shows the differential impact of individual AD risk factors on changes in the early intermediate phenotype after sequential tDCS in MCI patients. This research emphasizes the importance of precision medicine approaches in tDCS for the prodromal stages of AD.

COMT Val158Met and BDNF Val66Met Single-Nucleotide Polymorphisms Are Not Associated With Emotional Distress One Year After Moderate-Severe Traumatic Brain Injury.

Emotional distress is a common, but poorly addressed, feature of moderate-severe traumatic brain injury (TBI). Previously identified sociodemographic, psychological, and injury-related factors account for only a small proportion of the variability in emotional distress post-TBI. Genetic factors may help to further understand emotional distress in this population. The catechol-O-methyltransferase (COMT) Val158 and brain-derived neurotrophic factor (BDNF) 66Met single-nucleotide polymorphisms (SNPs) have been identified as possible contributory factors to outcomes after TBI. We investigated whether the COMT Val158 and BDNF 66Met SNPs were associated with emotional distress 1 year after moderate-severe TBI, and whether these associations were moderated by age, sex, and TBI severity (as measured by the duration of post-traumatic amnesia [PTA]). Moderate-severe TBI survivors (COMT, n = 391; BDNF, n = 311) provided saliva samples after admission to a TBI rehabilitation hospital. At a follow-up interview ∼1 year after injury, participants completed a self-report measure of emotional distress (Hospital Anxiety and Depression Scale; HADS). Multiple linear regression models were constructed for each SNP to predict total scores on the HADS. Neither COMT Val158 nor BDNF 66Met carriage status (carrier vs. non-carrier) significantly predicted emotional distress (COMT, p = 0.49; BDNF, p = 0.66). Interactions of SNP × age (COMT, p = 0.90; BDNF, p = 0.93), SNP × sex (COMT, p = 0.09; BDNF, p = 0.60), SNP × injury severity (COMT, p = 0.53; BDNF, p = 0.87), and SNP × sex × age (COMT, p = 0.08; BDNF, p = 0.76) were also non-significant. Our null findings suggest that COMT Val158 and BDNF 66Met SNPs do not aid the prediction of emotional distress 1 year after moderate-severe TBI, neither in isolation nor in interaction with age, sex and injury severity. The reporting of null findings such as ours is important to avoid publication bias and prompt researchers to consider the challenges of single-gene candidate studies in understanding post-TBI outcomes. Analyses in larger samples that incorporate multiple genetic factors and their relevant moderating factors may provide a greater understanding of the role of genetics in post-TBI emotional distress.

Association between the BDNF Val66Met polymorphism and major depressive disorder: a systematic review and meta-analysis.

Study objectives: This meta-analysis analytically reviewed recent studies concerning the potential associations between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and susceptibility to major depressive disorder (MDD), with subgroup analyses for race and age. Methods: Relevant case-control studies were systematically searched for in PubMed, Embase, the Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, and Sinomed databases. A total of 24 studies were finally identified to have reported outcomes including alleles, dominant genes, recessive genes, homozygosity, and heterozygosity. Subgroup meta-analyses were performed based on participant age and ethnicity. Publication bias was represented by funnel plots. All meta-analyses of the randomized controlled trials included for evaluation were performed using RevMan5.3 software. Results: The findings revealed no significant association between BDNF Val66Met polymorphism and MDD. However, the Met allele was found to be associated with genetic susceptibility to MDD among white populations on subgroup analysis (OR = 1.25, 95% CI: 1.05-1.48, P = 0.01). In the genetic model, dominant (OR = 1.40, 95% CI: 1.18-1.66, P = 0.0001), recessive (OR = 1.70, 95% CI: 1.05-2.78, P = 0.03), and homozygous (OR = 1.77, 95% CI: 1.08-2.88, P = 0.02) genes were all associated with MDD. Conclusions: Despite the outcome limitations, this meta-analysis confirmed that the BDNF Val66Met polymorphism is a susceptibility factor for MDD in white populations.

Brain-Derived Neurotrophic Factor rs6265 polymorphism is associated with severe cancer-related fatigue and neuropathic pain in female cancer survivors.

PURPOSE: This study examined the relationships between a single-nucleotide polymorphism (SNP) of brain-derived neurotrophic factor (BDNF) rs6265 and psychoneurological (PN) symptoms in female cancer survivors. METHODS: This secondary analysis examined 393 study participants. In addition to demographic variables, self-reported PN symptom scores (anxiety, bodily pain, depression, fatigue, neuropathic pain, and sleep disturbance) were collected using the Patient-Reported Outcomes Measurement Information System and 36-Item Short-Form Health Survey. Buccal swab samples were collected to obtain genotypes for BDNF rs6265 (Val/Val, Val/Met, or Met/Met). The PN symptom scores were compared across genotypes, and the relationships were examined using a regression model. We also explored correlations between different symptoms within each genotype. RESULTS: Participants with the Met/Met genotype reported significantly worse cancer-related fatigue and neuropathic pain, which was confirmed by rank-based regression analysis. In addition, cancer-related fatigue was correlated with other PN symptoms, particularly depression. These correlations were stronger in study participants with the Met/Met genotype than those with other genotypes. CONCLUSION: Our study suggests that female cancer survivors with the Met/Met genotype of BDNF rs6265 are likely to experience worse cancer-related fatigue and neuropathic pain and that cancer-related fatigue is a good predictor of co-occurring PN symptoms in this population. IMPLICATIONS FOR CANCER SURVIVORS: Our findings advance the scientific community's understanding of cancer-related PN symptoms experienced by female cancer survivors, especially the unique role of BDNF rs6265 polymorphism in these symptoms. Our findings offer valuable insights for clinical practice that the symptom experience among female cancer survivors may vary based on BDNF genotypes.

The Waist-Hip Ratio is a Mediator Between Serum Levels of Brain-Derived Neurotrophic Factor and Its Val66Met Polymorphism in Adolescents.

Aim: To explore anthropometric, metabolic and dietary factors associated with and their interplays with the Val66Met polymorphism at brain-derived neurotrophic factor (BDNF) gene (Bdnf) on serum BDNF levels in adolescents. Methods: Serum BDNF levels were quantified using an enzyme-linked immunosorbent assay in 644 high school students (278 males/366 females). A polymerase chain reaction and restriction fragment length polymorphism assay were utilized for Bdnf Val66Met genotyping followed by verification using DNA sequencing. Serum levels of metabolic characteristics were assayed by routine methods. The intake of macro and micronutrients was collected by a three-day food record. Results: Serum BDNF levels were found to be significantly different in the subjects with different genotypes of Bdnf Val66Met (Val/Val homozygotes, 60.05 ± 28.07 ng/mL vs Val/Met heterozygotes, 56.37 ± 29.34 ng/mL vs Met/Met homozygotes, 51.32 ± 24.54 ng/mL, p = 0.022). Among the 36 tested variables, waist-hip ratio (WHR) (ß = -0.163, p < 0.001), iodine intake (ß = 0.132, p = 0.001), heart rate (ß = 0.108, p = 0.005), high-density lipoprotein cholesterol (HDL-C) (ß = 0.098, p = 0.011) and dietary fiber intake (ß = 0.082, p = 0.084) were the predictor of serum BDNF levels, while SBP (ß = 0.097, p = 0.013) and WHR (ß = 0.091, p = 0.021) were related with Bdnf Val66Met. Moreover, WHR was observed to play a partial mediating role in the relationship between Bdnf Val66Met and serum BDNF levels (95% CI [-1.161, -0.087]) and contribute 13.05% of its total effect on serum BDNF levels. Conclusion: There are interplays between WHR and Bdnf Val66Met on serum BDNF levels, which may be among the explanations for the previous heterogeneous reports and provide novel insights into the regulation of serum BDNF levels.

Impaired fear memory in a rat model of the brain-derived neurotrophic factor Val66Met polymorphism is reversed by chronic exercise.

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release in the brain and has been implicated in fear and anxiety disorders, including post-traumatic stress disorder. Exercise has been shown to have benefits in affective disorders but the role of BDNF Val66Met remains unclear. Male and female BDNF Val66Met rats were housed in automated running-wheel cages from weaning while controls were housed in standard cages. During adulthood, all rats underwent standard three-day fear conditioning testing, with three tone/shock pairings on day 1 (acquisition), and extinction learning and memory (40 tones/session) on day 2 and day 3. Expression of BDNF and stress-related genes were measured in the frontal cortex. Extinction testing on day 2 revealed significantly lower freezing in response to initial cue exposure in control Met/Met rats, reflecting impaired fear memory. This deficit was reversed in both male and female Met/Met rats exposed to exercise. There were no genotype effects on acquisition or extinction of fear, however chronic exercise increased freezing in all groups at every stage of testing. Exercise furthermore led to increased expression of Bdnf in the prefrontal cortex of females and its isoforms in both sexes, as well as increased expression of FK506 binding protein 51 (Fkpb5) in females and decreased expression of Serum/glucocorticoid-regulated kinase (Sgk1) in males independent of genotype. These results show that the Met/Met genotype of the Val66Met polymorphism affects fear memory, and that chronic exercise selectively reverses this genotype effect. Chronic exercise also led to an overall increase in freezing in all genotypes which may contribute to results.

A Rat Model of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism Shows Attenuated Motivation for Alcohol Self-Administration and Diminished Propensity for Cue-Induced Relapse in Females.

Brain-derived neurotrophic factor (BDNF) has been implicated in alcohol use disorder. The Val66Met polymorphism is a common variant of the BDNF gene (rs6265) which reduces activity-dependent BDNF release, and has been suggested as a risk factor for psychiatric disorders and substance use. Using an operant self-administration paradigm, this study aimed to investigate ethanol preference and ethanol seeking in a novel rat model of the BDNF Val66Met polymorphism, Val68Met rats. Male and female BDNF Val68Met rats of three genotypes (Val/Val, Val/Met and Met/Met) were trained to lever press for a 10% ethanol solution. There was no effect of Val68Met genotype on acquisition of stable response to ethanol or its extinction. Met/Met rats of both sexes had a slight, but significantly lower breakpoint during progressive ratio sessions while female rats with the Met/Met genotype demonstrated a lower propensity for reinstatement of responding to cues. There were no effects of Val68Met genotype on anxiety-like behaviour or locomotor activity. In conclusion, Met/Met rats showed lower motivation to continue to press for a reward, and also a decreased propensity to relapse, suggesting a possible protective effect of the Met/Met genotype against alcohol use disorder, at least in females.

Moderate associations between BDNF Val66Met gene polymorphism, musical expertise, and mismatch negativity.

Auditory predictive processing relies on a complex interaction between environmental, neurophysiological, and genetic factors. In this view, the mismatch negativity (MMN) and intensive training on a musical instrument for several years have been used for studying environment-driven neural adaptations in audition. In addition, brain-derived neurotrophic factor (BDNF) has been shown crucial for both the neurogenesis and the later adaptation of the auditory system. The functional single-nucleotide polymorphism (SNP) Val66Met (rs6265) in the BDNF gene can affect BDNF protein levels, which are involved in neurobiological and neurophysiological processes such as neurogenesis and neuronal plasticity. In this study, we hypothesised that genetic variation within the BDNF gene would be associated with different levels of neuroplasticity of the auditory cortex in 74 musically trained participants. To achieve this goal, musicians and non-musicians were recruited and divided in Val/Val and Met- (Val/Met and Met/Met) carriers and their brain activity was measured with magnetoencephalography (MEG) while they listened to a regular auditory sequence eliciting different types of prediction errors. MMN responses indexing those prediction errors were overall enhanced in Val/Val carriers who underwent intensive musical training, compared to Met-carriers and non-musicians with either genotype. Although this study calls for replications with larger samples, our results provide a first glimpse of the possible role of gene-regulated neurotrophic factors in the neural adaptations of automatic predictive processing in the auditory domain after long-term training.

Diminished activity-dependent BDNF signaling differentially causes autism-like behavioral deficits in male and female mice.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. Recent human genetic studies have identified multiple high-risk genes for ASD, which produce similar phenotypes, indicating that diverse genetic factors converge to common molecular pathways. We and others have hypothesized that activity-dependent neural signaling is a convergent molecular pathway dysregulated in ASD. However, the causal link between diminished activity-dependent neural signaling and ASD remains unclear. Brain-derived neurotrophic factor (BDNF) is a key molecule mediating activity-dependent neural signaling. We therefore hypothesize that diminished activity-dependent BDNF signaling could confer autism-like behavioral deficits. Here, we investigated the effect of diminished activity-dependent BDNF signaling on autism-like behavioral deficits by using mice with genetic knock-in of a human BDNF methionine (Met) allele, which has decreased activity-dependent BDNF release without altering basal BDNF level. Compared with wild-type (WT) controls, diminished activity-dependent BDNF signaling similarly induced anxiety-like behaviors in male and female mice. Notably, diminished activity-dependent BDNF signaling differentially resulted in autism-like social deficits and increased self-grooming in male and female mice, and male mice were more severe than female mice. Again, sexually dimorphic spatial memory deficits were observed in female BDNF+/Met mice, but not in male BDNF+/Met mice. Our study not only reveals a causal link between diminished activity-dependent BDNF signaling and ASD-like behavioral deficits, but also identifies previously underappreciated sex-specific effect of diminished activity-dependent BDNF signaling in ASD. These mice with genetic knock-in of the human BDNF Met variant provide a distinct mouse model for studying the cellular and molecular mechanisms underlying diminished activity-dependent neural signaling, the common molecular pathway dysregulated in ASD.

Association between chronic tinnitus and brain-derived neurotrophic factor antisense RNA polymorphisms linked to the Val66Met polymorphism in BDNF.

Tinnitus is the sound heard in the ear or head of a person in the absence of external stimuli. Its etiopathogenesis is still not fully understood and the etiological causes responsible for tinnitus are quite variable. Brain-derived neurotrophic factor (BDNF) is one of the key neurotrophic factors in the growth, differentiation, and survival of neurons and in the developing auditory pathway, including the inner ear sensory epithelium. The regulation of BDNF gene is known to be managed by BDNF antisense (BDNF-AS) gene. BDNF-AS is located downstream of the BDNF gene and transcribes a long non-coding RNA. Inhibition of BDNF-AS upregulates BDNF mRNA, which increases protein levels and stimulates neuronal development and differentiation. Thus, BDNF and BDNF-AS both may play roles in the auditory pathway. Polymorphisms in both genes may have impact on hearing performance. A link was suggested between tinnitus and BDNF Val66Met polymorphism. However, there is no study questioning the relationship of tinnitus with BDNF-AS polymorphisms linked with BDNF Val66Met polymorphism. Therefore, this study aimed to scrutinize the role of BDNF-AS polymorphisms showing linkage with the BDNF Val66Met polymorphism in the course of tinnitus pathophysiology. Six BDNF-AS polymorphisms were analyzed on the tinnitus patients (n = 85) and the control subjects (n = 60) by Fluidigm Real-Time PCR using the Fluidigm Biomark microfluidic platform. When BDNF-AS polymorphisms were compared between the groups in terms of genotype and gender distribution, statistically significant differences were detected in rs925946, rs1519480, and rs10767658, polymorphisms (p less than 0.05). When the polymorphisms were compared by the duration of tinnitus, significant differences were found in rs925946, rs1488830, rs1519480, and rs10767658 polymorphisms (p less than 0.05). According to genetic inheritance model analysis, 2.33 and 1.53-fold risks were found for the rs10767658 polymorphism in the recessive and the additive models, respectively. For the rs1519480 polymorphism, a 2.25 fold risk was observed in the additive model. For the rs925946 polymorphism, 2.44 fold protective effect in dominant model, and 0.62 fold risk was found in the additive model. In conclusion, four of the polymorphisms in BDNF-AS gene (rs955946, rs1488830, rs1519480, and rs10767658) are potential gene loci that may play a role in the auditory pathway and affect auditory performance.